CYCLOPAMINE LACTAM ANALOGS AND METHODS OF USE THEREOF

• US 20080287420A1
• Filed: 03/07/2008
• Published: 11/20/2008
• Est. Priority Date: 03/07/2007
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Grogan, Michael J., Lescarbeau, Andre, Tremblay, Martin, Castro, Alfredo
• Granted Patent: US 7,964,590 B2
• Time in Patent Office: Days
• US Class Current: 514/212.02
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/06 having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 491/20 Spiro-condensed systems

Abstract

The present invention relates to steroidal alkaloids useful in the treatment of hedgehog pathway related disorders, particularly cancer.

Claims

1. A compound of Formula 1:

2. The compound of claim 1, wherein R⁷, R⁸, R¹² and R¹³ are H.

3. The compound of claim 1, wherein R⁴ and R⁵ are both H;

or R⁴ and R⁵ taken together form ═

O.

4. The compound of claim 1, wherein R² and R³ taken together form a bond.

5. The compound of claim 1, wherein R⁹ and R¹⁰ are each H;

or R⁹ and R¹⁰ taken together form ═

O or ═

S.

6. The compound of claim 4, wherein R⁴ and R⁵ are both H.

7. The compound of claim 4, wherein R⁹ and R¹⁰ taken together form ═

O or ═

S.

8. The compound of claim 4, wherein R⁷, R⁸, R¹² and R¹³ are H.

36. A pharmaceutical composition comprising a compound of claim 1, and at least one pharmaceutically acceptable excipient.

37. A method of treating a condition mediated by the hedgehog pathway, the method comprising administering to a subject an effective amount of a compound of claim 1.

38. The method of claim 37, wherein the condition mediated by the hedgehog pathway is cancer.

39. The method of claim 38, wherein the cancer is a cancer of the central nervous system, gastrointestinal tract, a hematological cancer, or leukemia.

40. The method of claim 38, wherein the cancer is selected from pancreatic cancer, medulloblastoma, multiple myeloma, myeloid leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, Hodgkin'"'"'s disease, and acute lymphocytic leukemia.

9. A compound of formula 9:

10. The compound of claim 9, wherein X is —

CH₂—

.

11. The compound of claim 9, wherein R⁶ is H or alkyl.

12. The compound of claim 9, wherein R¹ is H, optionally substituted C1-C6 alkyl, C(O)R²⁰, SO₂R²⁰, or it is COOR²⁰.

13. The compound of claim 9, wherein R⁹ and R¹⁰ taken together form ═

O or ═

S.

14. A compound selected from the group consisting of:

15. A compound of formula 15:

16. The compound of claim 15, wherein A is —

N(R¹³)— and

B is C═

O.

17. The compound of claim 15, wherein R¹¹ and R¹² are each H.

18. The compound of claim 15, wherein R² and R³ taken together form a bond.

19. The compound of claim 15, wherein R⁷ and R¹⁰ are each H.

20. The compound of claim 15, wherein B is —

N(R¹³)— and

A is C═

O.

25. A pharmaceutical composition comprising a compound of claim 15, and at least one pharmaceutically acceptable excipient.

26. A method of inhibiting activation of a hedgehog pathway in a patient diagnosed with a hyperproliferative disorder, comprising administering to said patient a compound of claim 15 in an amount sufficient to reduce the activation of the hedgehog pathway in a cell of said patient.

27. The method of claim 26, wherein said hyperproliferative disorder is cancer.

28. A method of treating a condition mediated by the hedgehog pathway, the method comprising administering to a subject an effective amount of a compound of claim 15.

29. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound of claim 15.

30. A method of treating cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 15.

31. The method of claim 30, wherein the cancer is a cancer of the central nervous system.

32. The method of claim 30, wherein the cancer is a cancer of the gastrointestinal tract.

33. The method of claim 30, wherein the cancer is a hematological cancer.

34. The method of claim 30, wherein the cancer is leukemia.

35. The method of claim 30, wherein the cancer is selected from pancreatic cancer, medulloblastoma, multiple myeloma, myeloid leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, Hodgkin'"'"'s disease, and acute lymphocytic leukemia.

21. A compound of formula 21:

22. The compound of claim 21, wherein X is —

CH₂—

.

23. The compound of claim 21, wherein said compound has formula 23:

24. A compound selected from the group consisting of: